SummaryNeural stem cell (NSC) transplantation can influence immune responses and suppress inflammation in the CNS. Metabolites, such as succinate, modulate the phenotype and function of immune cells, but whether and how NSCs are also activated by such immunometabolites to control immunoreactivity and inflammatory responses is unclear. Here, we show that transplanted somatic and directly induced NSCs ameliorate chronic CNS inflammation by reducing succinate levels in the cerebrospinal fluid, thereby decreasing mononuclear phagocyte (MP) infiltration and secondary CNS damage. Inflammatory MPs release succinate, which activates succinate receptor 1 (SUCNR1)/GPR91 on NSCs, leading them to secrete prostaglandin E2 and scavenge extracellular succinate with consequential anti-inflammatory effects. Thus, our work reveals an unexpected role for the succinate-SUCNR1 axis in somatic and directly induced NSCs, which controls the response of stem cells to inflammatory metabolic signals released by type 1 MPs in the chronically inflamed brain.

Neural stem cell (NSC) transplantation induces recovery in animal models of central nervous system (CNS) diseases. Although the replacement of lost endogenous cells was originally proposed as the primary healing mechanism of NSC grafts, it is now clear that transplanted NSCs operate via multiple mechanisms, including the horizontal exchange of therapeutic cargoes to host cells via extracellular vesicles (EVs). EVs are membrane particles trafficking nucleic acids, proteins, metabolites and metabolic enzymes, lipids, and entire organelles. However, the function and the contribution of these cargoes to the broad therapeutic effects of NSCs are yet to be fully understood. Mitochondrial dysfunction is an established feature of several inflammatory and degenerative CNS disorders, most of which are potentially treatable with exogenous stem cell therapeutics. Herein, we investigated the hypothesis that NSCs release and traffic functional mitochondria via EVs to restore mitochondrial function in target cells. Untargeted proteomics revealed a significant enrichment of mitochondrial proteins spontaneously released by NSCs in EVs. Morphological and functional analyses confirmed the presence of ultrastructurally intact mitochondria within EVs with conserved membrane potential and respiration. We found that the transfer of these mitochondria from EVs to mtDNA-deficient L929 Rho0 cells rescued mitochondrial function and increased Rho0 cell survival. Furthermore, the incorporation of mitochondria from EVs into inflammatory mononuclear phagocytes restored normal mitochondrial dynamics and cellular metabolism and reduced the expression of pro-inflammatory markers in target cells. When transplanted in an animal model of multiple sclerosis, exogenous NSCs actively transferred mitochondria to mononuclear phagocytes and induced a significant amelioration of clinical deficits. Our data provide the first evidence that NSCs deliver functional mitochondria to target cells via EVs, paving the way for the development of novel (a)cellular approaches aimed at restoring mitochondrial dysfunction not only in multiple sclerosis, but also in degenerative neurological diseases.

Ischemic stroke continues to be a leading cause of morbidity and mortality throughout the world. To protect and/or repair the ischemic brain, a multitiered approach may be centered on neural stem cell (NSC) transplantation. Transplanted NSCs exert beneficial effects not only via structural replacement, but also via immunomodulatory and/or neurotrophic actions. Unfortunately, the clinical translation of such promising therapies remains elusive, in part due to their limited persistence/survivability within the hostile ischemic microenvironment. Herein, we discuss current approaches for the development of NSCs more amenable to survival within the ischemic brain as a tool for future cellular therapies in stroke.

Ozone therapy has been widely used in everyday clinical practice over the last few years, leading to significant clinical results in the treatment of herniated discs and pain management. Nevertheless, further studies have demonstrated its potential efficacy and safety under other clinical and experimental conditions. However, some of these studies showed controversial results regarding the safety and efficacy of ozone therapy, thus mining its potential use in an everyday clinical practice. To this regard, it should be considered that extensive literature review reported the use of ozone in a significant different dose range and with different delivery systems. The aim of the present review is to describe the various pharmacological effects of ozone in different organs and clinical conditions and to provide possible biochemical and molecular insights for ozone biological properties, thus providing a possible explanation for various controversial clinical outcomes described in the scientific literature.

Adult stem cells are fundamental to maintain tissue homeostasis, growth, and regeneration. They reside in specialized environments called niches. Following activating signals, they proliferate and differentiate into functional cells that are able to preserve tissue physiology, either to guarantee normal turnover or to counteract tissue damage caused by injury or disease. Multiple interactions occur within the niche between stem cell-intrinsic factors, supporting cells, the extracellular matrix, and signaling pathways. Altogether, these interactions govern cell fate, preserving the stem cell pool, and regulating stem cell proliferation and differentiation. Based on their response to body needs, tissues can be largely classified into three main categories: tissues that even in normal conditions are characterized by an impressive turnover to replace rapidly exhausting cells (blood, epidermis, or intestinal epithelium); tissues that normally require only a basal cell replacement, though able to efficiently respond to increased tissue needs, injury, or disease (skeletal muscle); tissues that are equipped with less powerful stem cell niches, whose repairing ability is not able to overcome severe damage (heart or nervous tissue). The purpose of this review is to describe the main characteristics of stem cell niches in these different tissues, highlighting the various components influencing stem cell activity. Although much has been done, more work is needed to further increase our knowledge of niche interactions. This would be important not only to shed light on this fundamental chapter of human physiology but also to help the development of cell-based strategies for clinical therapeutic applications, especially when other approaches fail.

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Advances in functional imaging are supporting neurosurgery and radiotherapy for glioblastoma, which still remains the most aggressive brain tumor with poor prognosis. The typical infiltration pattern of glioblastoma, which impedes a complete surgical resection, is coupled with a high rate of invasiveness and radioresistance, thus further limiting efficient therapy, leading to inevitable and fatal recurrences. Hypoxia is of crucial importance in gliomagenesis and, besides reducing radiotherapy efficacy, also induces cellular and molecular mediators that foster proliferation and invasion. In this review, we aimed at analyzing the biological mechanism of glioblastoma invasiveness and radioresistance in hypoxic niches of glioblastoma. We also discussed the link between hypoxia and radiation-induced radioresistance with activation of SRC proto-oncogene non-receptor tyrosine kinase, prospecting potential strategies to overcome the current limitation in glioblastoma treatment.

Cell-to-cell interaction and cell-to-extracellular environment communication are emerging as new therapeutic targets in neurodegenerative disorders. Dynamic expression of connexins leads to distinctive hemichannels and gap junctions, characterized by cell-specific conduction, exchange of stimuli or metabolites, and particular channel functions. Herein, we briefly reviewed classical physiological traits and functions of connexins, hemichannels, and gap junctions, in order to discuss the controversial role of these proteins and their mediated interactions during neuroprotection, with a particular focus on Cx43-based channels. We pointed out the contribution of connexins in neural cells populations during neurodegenerative processes to explore potential neuroprotective therapeutic applications.